The effectiveness and value of tirzepatide for type 2 diabetes mellitus

CVOTs

Type 2 diabetes mellitus (T2DM) is an endocrine disorder that impairs the body's ability to regulate blood glucose levels. Chronic hyperglycemia can lead to microvascular (eg, retinopathy, nephropathy, neuropathy) and macrovascular (eg, coronary artery disease, stroke) complications. 1 More than 34 million Americans have diabetes; racial and ethnic minority patients experience a disproportionate burden of disease because of higher prevalence rates, worse glycemic control, and higher rates of complications. 2 The annual medical treatment and productivity costs of diagnosed diabetes are rapidly increasing and were last estimated in 2017 to be $327 billion. 3 Glycated hemoglobin A1c (A1c) is a common measurement of glycemic control; an A1c target of less than 7.0% is appropriate for most adults with T2DM. In addition to comprehensive lifestyle modifications, first-line drug therapy for T2DM for most patients includes metformin. However, in patients with or at high risk for atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, a sodium-glucose cotransporter 2 inhibitor and/or glucagon-like peptide 1 (GLP-1) receptor agonist (RA) can be considered as an initial therapy, irrespective of baseline A1c or metformin use, because of the demonstrated cardiovascular benefit of these 2 classes of drugs. 4 Tirzepatide is a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA and is expected to receive US Food and Drug Administration approval for the treatment of T2DM in 2022. The Institute for Clinical and Economic Review (ICER) performed a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of tirzepatide for the treatment of T2DM. Here, we present the summary of our findings and highlights of the policy discussion with key stakeholders that took place at a public meeting of the New England Comparative Effectiveness Public Advisory Council (NE CEPAC) on January 20, 2022. The detailed report is available on the ICER website. 5

CLINICAL EFFECTIVENESS
We compared the clinical effectiveness of adding tirzepatide, injectable semaglutide (Ozempic, Novo Nordisk), or empagliflozin (Jardiance, Boehringer Ingelheim, and Eli Lilly) to background therapy (metformin ± sulfonylureas or thiazolidinediones) to background therapy alone. We examined head-tohead trials when available. In addition, we conducted a Bayesian network meta-analysis (NMA) using 5 randomized controlled trials. 6-10 Therapies were evaluated using estimated treatment differences between tirzepatide and its comparators on the intermediate outcomes of change from baseline in A1c, weight, low-density lipoprotein cholesterol (LDL-C), and systolic blood pressure (SBP) at 40 weeks. Additionally, we examined data from the SURPASS-4 trial to assess The effectiveness and value of tirzepatide for type 2 diabetes mellitus tirzepatide's cardiovascular safety vs insulin glargine and qualitatively compare its impact on major adverse cardiovascular events (MACEs) to the published cardiovascular outcome trials (CVOTs) for semaglutide and empagliflozin. [11][12][13] Our evaluation of tirzepatide used data from a 26-week phase 2 trial and the NMA. Both demonstrated tirzepatide's superiority over background therapy, with greater reduction in A1c (−2.5% to −1.7%) and weight (−10.9 kg to −9.5 kg). A significant treatment difference in LDL-C (−4.3 mg/dL) and SBP (−7.5 mmHg) was observed in the NMA results but not in the phase 2 trial. The most frequent adverse events associated with tirzepatide in the phase 2 trial were gastrointestinal-related (nausea, vomiting, and diarrhea) and were mild to moderate in severity. 14 The SURPASS-2 trial 6 allowed for a direct comparison of tirzepatide and semaglutide. Participants treated with tirzepatide 15 mg had a greater mean change at 40 weeks in A1c (−2.3%) than those treated with semaglutide 1 mg (−1.86%), with an estimated absolute treatment difference of −0.45%. Tirzepatide also demonstrated a greater reduction in weight (−5.5 kg) and SBP (−2.9 mmHg) vs semaglutide. A larger proportion of patients treated with tirzepatide achieved a weight loss of 15% or more compared with patients treated with semaglutide (36% vs 8%, respectively), and these patients also had greater improvements in 3 weight-related quality-of-life measures. 15 Rates of gastrointestinal adverse events, hypoglycemia (glucose ≤ 54 mg/dL), injection-site reactions, and treatment-related discontinuations were slightly higher with tirzepatide than with semaglutide.
For the comparison of tirzepatide and empagliflozin, NMA results showed superior outcomes for tirzepatide at 40 weeks in A1c (−1.1%), weight (−7.2 kg), LDL-C (−7.5 mg/dL), and SBP (−2.6 mmHg). Comparisons could not be made between the 2 treatments on quality of life or safety.
In the SURPASS-4 cardiovascular safety trial, the pooled cohort of patients treated with 5 mg, 10 mg, and 15 mg of tirzepatide was compared to patients treated with insulin glargine. The results showed a trend toward benefit with tirzepatide in both groups, but the trial was not powered to evaluate superiority. Published CVOTs have demonstrated a significant reduction in the occurrence of MACE-3 (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) for both semaglutide (hazard ratio [HR] = 0.74; 95% CI = 0.58 to 0.95) and empagliflozin (HR = 0.86; 95% CI = 0.74 to 0.99).
Limitations of the Clinical Evidence. Although tirzepatide shows efficacy in intermediate outcomes such as A1c, and the SURPASS-4 trial showed promising results, it was a cardiovascular outcomes safety trial and, thus, not powered to evaluate differences in MACE. The SURPASS-CVOT, set to be complete in late 2024, will provide greater certainty on tirzepatide's impact on important cardiovascular and renal outcomes.
Additionally, we have only moderate certainty regarding the comparative effectiveness of tirzepatide vs empagliflozin because of our reliance on indirect comparisons through an NMA, an approach that is susceptible to residual confounding bias. Tirzepatide and empagliflozin have different mechanisms of action, and it remains to be seen whether the net benefits of tirzepatide over empagliflozin in intermediate outcomes will carry over to long-term cardiovascular and renal benefit. Finally, because of tirzepatide's novel mechanism of action combining GIP with GLP-1, there is uncertainty about long-term safety, although short-term data suggest no major concerns.

LONG-TERM COST-EFFECTIVENESS
We calculated the lifetime cost-effectiveness of adding tirzepatide, semaglutide, and empagliflozin to background therapy vs background therapy alone. We developed a patient-level event microsimulation based on United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS-OM2) risk equations and ICER's prior T2DM model. 16,17 Our model cohort included 387 US-based patients with clinical characteristics derived from multiple National Health and Nutrition Examination Surveys spanning 2013-2018. Model inputs were derived from the NMA results on intermediate outcomes and CVOT cardiovascular outcome HRs, as available. A health care system perspective was used as the base case, and outcomes included quality-adjusted life years (QALYs) gained, life years (LYs) gained, and total lifetime costs; these costs and outcomes were discounted at an annual rate of 3% over a lifetime time horizon.
The price and data on long-term cardiovascular outcomes for tirzepatide were unavailable at the time of analysis and required the use of placeholder values. The annual net price of tirzepatide was set equal to semaglutide ($4,643.50 per year). Tirzepatide's impact on MACEs was adjusted in the model by applying HRs, calculated from SURPASS-4, to the event equations; no adjustment was made to the congestive heart failure and nephropathy impacts of tirzepatide because of lack of clinical evidence.
Using the placeholder price, tirzepatide treatment vs background therapy alone resulted in a greater number of QALYs and LYs gained and met the incremental costeffectiveness thresholds of $100,000 per QALY and LY (Table 1). Tirzepatide did not produce large differences in QALYs and LYs gained vs semaglutide (0.05 incremental QALYs and −0.17 LYs) or empagliflozin (0.30 incremental QALYs and 0.19 LYs), all with overlapping credible ranges. This uncertainty is in part due to tirzepatide's immature clinical evidence base on heart failure and renal outcomes. during which representatives from insurers and manufacturers join clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations.
The ICER report on tirzepatide for T2DM was the subject of a NE CEPAC meeting on January 20, 2022. Following the discussion, the CEPAC members deliberated on key questions raised by ICER's report. The panel unanimously (13 of 13) voted that the current available evidence is adequate to demonstrate that tirzepatide provides a superior net health benefit compared with background therapy alone. A small majority (7 of 13) voted that the evidence was not adequate to demonstrate that tirzepatide added to background therapy is superior to injectable semaglutide, citing unknowns on potential long-term harms and the pending results from the ongoing CVOT trial. Finally, a strong majority of panel members (10 of 12) voted that the current evidence is not adequate to demonstrate superiority of tirzepatide to that of empagliflozin because of the lack of head-to-head trials and the demonstrated cardiovascular and renal benefits of empagliflozin. One panel member abstained from the vote.
The panel also voted on "other potential benefits" and "contextual considerations" as part of the process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical-and/or cost-effectiveness. The results of the vote Limitations of the Long-Term Cost-Effectiveness. The UKPDS-OM2 was developed using patient data from a cohort that is different from the US T2DM population; our modeled patient cohort had a greater average body weight and smaller proportion of White participants, with exposure to treatments different from those available to the UKPDS-OM2 cohort from 1977 to 1991. 18 Sensitivity analyses identified the annual cost of tirzepatide and MACE HR vs background therapy to be the key drivers of cost-effectiveness results. The wide credible ranges of the incremental cost-effectiveness ratios shown in Table 1 and our use of estimates for price and MACE HR limit any definitive conclusions on the cost-effectiveness of tirzepatide against active comparators.

Policy Discussion
The NE CEPAC is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical-and cost-effectiveness of health care interventions. The NE CEPAC is composed of medical evidence experts, including practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review, as well as formal comment from manufacturers and the public. A policy roundtable concludes each meeting,  Results for Tirzepatide and Comparators and Incremental Results  of Tirzepatide vs Comparators   TABLE 1 Recommendation 3. Manufacturers should seek to set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments. In the setting of T2DM, there is increasing emphasis on potential benefits beyond A1c, such as weight loss and prevention of cardiovascular events and kidney disease. Manufacturer pricing at launch should reflect these considerations and whether longer-term cardiovascular and renal outcomes have been demonstrated.

Base-Case
Recommendation 4. Manufacturers should take steps to increase the diversity of participants in their clinical trials for T2DM. Given the high overall prevalence of T2DM in the United States and the higher prevalence in racial and ethnic minority populations, it is unacceptable that clinical trials still largely consisted of non-Hispanic White participants.
Recommendation 5. More research is needed to generate quality-of-life data and data for use in economic evaluations regarding the societal costs of diabetes. For use in an economic model, it would be particularly useful if costs were stratified by patient characteristics, such as age, race and ethnicity, and years since diagnosis. Importantly for diabetes, costs specific to diabetes-related complications, such as cardiovascular and renal events, are important for accurate economic modeling of the societal perspective.
Recommendation 6. All stakeholders have a responsibility to ensure that effective new treatment options for patients with T2DM are introduced in a way that will help reduce health inequities. For example, manufacturers should ensure that that the set price for new treatments is in fair are shown in Table 2. They highlight several factors beyond the results of cost-effectiveness modeling that the CEPAC panel felt were particularly important for judgments of overall long-term value for money. The policy roundtable discussion explored how best to translate the evidence and additional considerations into clinical practice and into pricing and insurance coverage policies. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website. 5 Several key policy perspectives include the following recommendations: Recommendation 1. Payers should consider broadening criteria for coverage of both GLP-1 RAs and SGLT-2 inhibitors since, based on the most current clinical guidelines, 19,20 these drugs may be considered first-line therapy in T2DM patients with cardiovascular or renal disease, and wider use should be encouraged in these specific populations. Tirzepatide may be considered as either a GLP-RA or a separate class for the purposes of coverage. Recommendation 2. Payers should only use step therapy when it provides adequate flexibility to meet the needs of diverse patients and when implementation can meet high standards of transparency and efficiency. Given the recommendations of the most recent clinical guidelines, 19,20 payers should consider access to drugs with proven cardiovascular or renal benefit without requiring a trial of metformin therapy; if step therapy with metformin is established, options from both GLP-1 RA and SGLT-2 inhibitor classes should be preserved as the next step.